PROJECT SUMMARY Natural products continue to be excellent and productive sources of new drug candidates or lead compounds for treatment of neurological disease. This proposal focuses on the synthesis and biological characterization of promising new small molecules known as mellpaladines, which are marine natural products that exhibit specificity for the 5-HT (serotonin) family of G protein-coupled receptors (GPCRs). Serotonin receptors have been successfully targeted for therapeutic treatment of a variety of neurological and non-CNS pathologies. However, the effective assessment of the clinical relevance of several 5-HT receptor family members is stalled due to lack of selective pharmacological tools. To this end, we propose development of mellpaladines A and B, which are antagonists of 5-HT5A and 5-HT7 receptors, to fulfill this role. Our long-term objective is to develop mellpaladines A/B and natural and synthetic analogs as novel pharmacological tools for characterization of 5- HT receptors, and explore their potential as new therapeutic candidates in neuropsychiatric disease. This high risk, high reward project will support a key first step in this process: synthesis of the molecule and initial validation of CNS activity. This proposal brings together the complementary natural products chemistry and neuropharmacological expertise of the Scheidt and Swanson laboratories, respectively, at Northwestern University. The objectives will be to: (1) synthesize and validate the structural assignment of mellpaladines A and B, and (2) validate and optimize interspecies functional inhibition against 5-HT5A/7 receptors. This project will yield novel chemical tools for the pharmacological manipulation of serotonin receptors and may lead to new therapeutic strategies for neurological disease.